Progression of cancers to the metastatic state involves multiple cellular and genetic changes. Acquisition of metastatic ability requires loss of metastasis suppressor functions, as well as activation of metastasis promoting functions. Starting from the chromosome mapping of metastasis suppressor genes, followed by a combination of positional and functional cloning strategies, we identified KAI1, a human gene that suppresses the metastatic ability in a rat prostate cancer model. The significance of KAI1 in human tumor metastasis was shown by the marked decrease in KAI1 expression in metastatic tumors of various tissue origins compared with their normal or non-metastatic counterparts, suggesting KAI1 as an excellent diagnostic and prognostic marker. Identification of the KAI1 binding partners (e.g., E-cadherin and catenins) by yeast two-hybrid and co-immunoprecipitation assays provided clues to molecular details of the KAI1 function. By using the same experimental system, we have recently cloned another metastasis suppressor gene, termed Tey1, on human chromosome 8p21, where LOH is frequently observed in many types of human cancers. Cellular and molecular mechanisms by which Tey1 suppresses metastasis are under investigation. We are also investigating, by genome-wide gene expression profiling, downstream target genes that are controlled by KAI1- and Tey1-regulated signaling pathways.We recently developed a Kai1 knockout mouse which we plan to use to assess the role of this protein in normal and cancer cell function.